Retinoic acid (t-RA) is an important regulator of cell growth and differentiation in both the adult and developing embryo. The effects of t-RA are mediated through the retinoic acid receptor (RAR) that binds all-trans-RA (t-RA) but the underlying mechanism is still not known [106]. Using Steered Molecular Dynamics (SMD) [100] we studied the transition between the bound and unbound form of the retinoic acid receptor, known from experiment to be accompanied by a conformational change that enables the hormone-receptor complex to bind to specific sequences of DNA and other transcriptional coactivators or repressors*. The crystal structure of the ligand binding domain (the receptor domain responsible for recognizing and binding the hormone) of the human retinoic acid receptor hRAR-( bound to all-trans retinoic acid [107] was used for simulating different unbinding pathways. Examination of the crystal structure of the hRAR-( bound to t-RA suggests three entry/exit points for the hormone that were explored using SMD. In all simulations, the protein-ligand system was surrounded by a water bath, the total number of atoms being (15,000. One atom of the hormone was harmonically restrained (K=10 kcal mol-1/E2) to a point moving with a constant velocity v=0.032 E/ps in a chosen direction. The molecular dynamics program NAMD [19], was used to compute three different trajectories of 750 ps each. The results of our simulations show that, if strong enough forces are applied, it is possible to extract the hormone out of the binding pocket, with little or almost no effect on the protein structure. Along one of the pathways the hormone has to overcome the strong electrostatic forces between its carboxylate group and the charged Lys and Arg residues lining the opening. In the other two cases, before the hormone is completely out of the protein, the carboxylate group of the hormone interacts strongly with some of the neighboring residues. It may indicate that those residu es are the ones to attract and guide the hormone toward the binding pocket. Further studies of the unbinding mechanism will be conducted using the Targeted Molecular Dynamics (TMD) method [105]. TMD imposes time-dependent holonomic constraints that drive the system from the bound to the unbound state. The resulting pathways may be used for choosing the direction of the applied force in SMD simulations.